Chemotherapeutic agents that compromise the integrity of nucleic acid are important components in modern medical efforts to combat hyperproliferative diseases, such as cancer and autoimmune dysfunctions as well as viral and microbial infections. Many compounds, such as BCNU, cyclophosphamide, and cisplatin are effective chemotherapeutic agents because they significantly modify nucleic acid and inhibit DNA synthesis and/or DNA repair to prevent cellular proliferation. However, the widespread use of these agents is limited by two major complications. First, they are non-selective DNA damaging agents. Second, these agents induce lesions that if inappropriately replicated can cause further mutagenic events to potentiate oncogenesis. Translesion DNA synthesis also represents a possible route for the initiation of drug resistance, genetic variations associated with solid tumors, and the development of secondary cancers.
These concerns have prompted the design of more selective drugs that target specific enzymes involved in nucleic acid metabolism. Arguably, the more successful of these agents are nucleotide analogs, such as AZT and acyclovir that terminate DNA polymerization. The use of these agents is historically associated with the treatment of viruses, such as HIV and herpes simplex virus. However, they and other analogs, such as araC and fludarabine have also been used in the treatment of cancer. Unfortunately, the therapeutic utility of these nucleotide analogs is often limited by complications. The most prevalent of these complications is the excision of the enzymatically-inserted nucleotide from the primer-template to reverse chain termination, which allows for the re-initiation of DNA synthesis. Although viral polymerases use pyrophosphorolysis to remove chain terminators from DNA, eukaryotes use exonuclease proofreading activity to effectively excise the inserted chain terminator. Either activity provides a mechanism for drug resistance. Another complication is that these inhibitors contain alterations in the ribose moiety while the nucleobase portion remains identical to that of a natural nucleoside. As a consequence, there is an intrinsic lack of selectivity for inhibiting one DNA polymerase versus another. Since these agents resemble their natural counterparts, they may be degraded by cellular enzymes that metabolize natural nucleotides. For example, this complication limits the use of fludarabine and may play a significant role in the development of drug resistance to other natural nucleoside analogs.
Acute lymphocytic leukemia (ALL) is the most common form of childhood cancer. As with all cancers, a fundamental feature of ALL is its hyperproliferative nature that is defined by uncontrollable and pro-mutagenic DNA replication. Nucleoside analogues are effective anti-cancer agents against leukemia as they produce anti-proliferative and/or cytotoxic effects by inhibiting DNA replication. Despite their widespread utility, however, most nucleoside analogues possess very narrow therapeutic windows that can create significant clinical problems. This problem is exacerbated since it is nearly impossible to rapidly and accurately assess the efficacy of conventional nucleoside analogues. Patient responses to chemotherapy are typically gauged by qualitative criteria ranging from the absence of overt disease symptoms to quantifying the ratio of normal versus cancerous blood cells. These clinical end points can take weeks or even months to accurately define. As such, the inability to assess drug action on shorter time scales (hours or days) significantly hinders physicians from making informed decisions regarding optimal dosing regimens. For example analogue cordycepin (3′-deoxyadenosine) terminates DNA synthesis after its incorporation into DNA. This analogue produces cytotoxic effects against TdT-positive leukemia, especially when combined with the adenosine deaminase inhibitor, deoxycoformycin. Unfortunately, cordycepin also utilized by template-dependent DNA polymerases involved in chromosomal DNA synthesis. The ability of these polymerases to incorporate but not elongate cordycepin terminates DNA synthesis in both cancerous and healthy cells. This non-selective killing can cause adverse side effects such as immunosuppression, fatigue, nausea, vomiting, and alopecia.